Schott, Sarah ORCID: 0000-0002-1714-1147, Wimberger, Pauline, Klink, Barbara, Gruetzmann, Konrad, Puppe, Julian, Wauer, Ulrike Sophie, Klotz, Daniel Martin, Schroeck, Evelin and Kuhlmann, Jan Dominik (2017). The conjugated antimetabolite 5-FdU-ECyd and its cellular and molecular effects on platinum-sensitive vs. -resistant ovarian cancer cells in vitro. Oncotarget, 8 (44). S. 76935 - 76949. ORCHARD PARK: IMPACT JOURNALS LLC. ISSN 1949-2553

Full text not available from this repository.

Abstract

Background: Resistance to platinum-based chemotherapy is a clinical challenge in the treatment of ovarian cancer (OC) and limits survival. Therefore, innovative drugs against platinum-resistance are urgently needed. Our therapeutic concept is based on the conjugation of two chemotherapeutic compounds to a monotherapeutic pro-drug, which is taken up by cancer cells and cleaved into active cytostatic metabolites. We explore the activity of the duplex-prodrug 5-FdU-ECyd, covalently linking 2'-deoxy-5fluorouridine (5-FdU) and 3'-C-ethynylcytidine (ECyd), on platinum-resistant OC cells. Methods: In vitro assays and RNA-Sequencing were applied for characterization of 5-FdU-ECyd treated platinum-sensitive A2780 and isogenic platinum-resistant A2780cis and independent platinum-resistant Skov-3-IP OC cells. Results: Nano molar 5-FdU-ECyd concentrations induced a rapid dose-dependent decline of cell viability in platinum-sensitive and -resistant OC cells. The effect of 5-FdU-ECyd was accompanied by the formation of DNA double strand breaks and apoptosis induction, indicated by a strong increase of pro-apoptotic molecular markers. Moreover, 5-FdU-ECyd efficiently decreased migration of platinum-resistant OC cells and inhibited clonogenic or spheroidal growth. Transcriptome analysis showed early up-regulation of CDKN1A and c-Fos in both, platinum-resistant and -sensitive cells after 5-FdU-ECyd treatment and de-regulation of distinct cellular pathways involved in cell cycle regulation, apoptosis, DNA-damage response and RNA-metabolism. Combined treatment of 5-FdU-ECyd and cisplatin did not show a synergistic cellular response, suggesting the potential use of 5-FdU-ECyd as a monotherapeutic agent. Conclusion: Our data provide novel mechanistic insight into the anti-tumor effect of 5-FdU-ECyd and we hypothesize that this duplex-prodrug could be a promising therapeutic option for OC patients with resistance to platinum-based chemotherapy.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Schott, SarahUNSPECIFIEDorcid.org/0000-0002-1714-1147UNSPECIFIED
Wimberger, PaulineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klink, BarbaraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gruetzmann, KonradUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Puppe, JulianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Wauer, Ulrike SophieUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Klotz, Daniel MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schroeck, EvelinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Kuhlmann, Jan DominikUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-217303
DOI: 10.18632/oncotarget.20260
Journal or Publication Title: Oncotarget
Volume: 8
Number: 44
Page Range: S. 76935 - 76949
Date: 2017
Publisher: IMPACT JOURNALS LLC
Place of Publication: ORCHARD PARK
ISSN: 1949-2553
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
DNA-DAMAGE; CISPLATIN; FOS; RECURRENT; BEVACIZUMAB; ACTIVATION; MECHANISMS; INDUCTION; TAS-106; REPAIRMultiple languages
Oncology; Cell BiologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/21730

Downloads

Downloads per month over past year

Altmetric

Export

Actions (login required)

View Item View Item